The Specific Aim of Core A is to provide an integrated structure-guided lead identification and optimization effort, in collaboration with Projects 1?4 and Core B, with the ultimate objective of delivering advanced leads for entry into translational studies comprising early development (Core C) toward an Investigational New Drug IND filing, and preclinical regimen development and pharmacokinetic/pharmacodynamic (PKPD) studies (Project 4). This will be accomplished through two Activities: (1) Lead Identification, to identify a lead compound within a series, with demonstrated efficacy in Mycobacterium tuberculosis (Mtb)-infected mice, that is sufficiently well characterized to allow development of a clear lead optimization plan, and (2) Lead Optimization and Compound Prioritization, to optimize the lead(s) identified in Activity 1 to meet the criteria required to initiate non-GLP safety studies (in Core C), and proceed to regimen development in Project 4. To conduct these activities, Core A will provide capabilities including medicinal chemistry (design and synthesis); structural biology; computational chemistry; in vitro and in vivo absorption, distribution, metabolism and excretion (ADME) and pharmacokinetic (PK) studies; in vitro safety assays; preliminary toxicity studies, and scale-up synthesis. These capabilities will support selection of compounds from Projects 1?3, for further progression. together with evaluations of antituberculosis activity through Core B. The Core will innovate by providing state-of-the-art structural and computational approaches in designing small molecules and peptides and leverage the latest developments in understanding of oral bioavailability of large peptides and peptidomimetics. Effective direction and successful implementation of these capabilities and processes is critical to the overall goals of the CETR, which include selection of drug candidates against three drug targets, from Projects 1?3. Core A will be led by TB Alliance, which is ideally suited to the task, with extensive experience in drug discovery and development and a track record of success: the Core A PI, Dr. Upton, and the key personnel, have collectively over 100 years of experience within the pharmaceutical industry and TB Alliance in drug discovery and development. Over the last two years, the team has advanced four projects into IND-enabling studies and filed three INDs, with two more expected in 2018. The team also manages a mature portfolio of lead Identification and lead optimization projects. The Core will operate using the successful virtual R&D model of TB Alliance: All activities will be carried out with partners and contract research organizations (CROs). For each series, a unique, tailored program of studies will be developed where partners and CROs will be selected based on need, cost, quality, and timing, leveraging the expertise and specializations of the named organizations that will participate (such as Proteros and Schrodinger). This extremely flexible, nimble, and efficient setup will allow the Center to prosecute multiple projects with diverse needs, without being reliant on any one approach or provider. This setup is possible due to the experience and expertise of the Core staff in building and directing such programs for TB Alliance.